Safety and Efficacy Pilot Trial of the Anti-Viral and Anti-Tumor Activity of Velcade Combined With (R)ICE in Subjects With EBV and/or HHV-8 Positive Relapsed/Refractory AIDS-Associated Non-Hodgkin's Lymphoma
- Evaluate the safety and overall lymphoma response rate of bortezomib in combination
with ifosfamide, carboplatin, and etoposide (ICE) with or without rituximab in patients
with Epstein-Barr Virus (EBV)- and/or human herpes virus-8 (HHV-8)- positive relapsed
or refractory HIV-associated non-Hodgkin lymphoma (NHL).
- Evaluate the impact of bortezomib alone and in combination with rituximab) and ICE ([R]
ICE) on serum HIV viral loads and APOBEC3G levels.
- Estimate the impact of bortezomib alone and in combination with (R)ICE on EBV and HHV-8
lytic activation using serum viral loads.
- Estimate the median response duration and 1 year overall survival rate of patients
treated with this regimen.
- Evaluate the safety of bortezomib alone in patients with relapsed or refractory
- Correlate EBV/HHV-8 viral load changes with lymphoma response.
- Compare the above outcomes to a parallel protocol employing ICE with or without
rituximab in patients with EBV/HHV-8-negative AIDS-NHL to assess whether bortezomib has
additional effects beyond (R)ICE alone.
OUTLINE: This is a multicenter, dose-escalation study of bortezomib. Patients are assigned
to 1 of 2 treatment groups.
- CD20-negative patients
- Part A: Patients receive bortezomib IV over 3-5 seconds on days 1 and 8,
dexamethasone IV and etoposide IV over 2 hours on days 8-10, and ifosfamide IV
continuously over 24-hours and carboplatin IV over 2 hours on day 9. Treatment
repeats every 28 days until the maximum tolerated dose (MTD) is determined.
Patients who tolerate the MTD of bortezomib may move on to part B.
- Part B: Patients receive bortezomib IV over 3-5 seconds at the MTD on days 1 and
8, dexamethasone IV on days 1-3 and 8, etoposide IV over 2 hours on days 1-3, and
ifosfamide IV continuously over 24-hours and carboplatin IV over 2 hours on day 2.
Treatment repeats every 21 days for up to 6 courses in the absence of disease
progression or unacceptable toxicity. Some patients may undergo hematopoietic stem
cell transplantation (HSCT).
- CD20-positive patients
- Part A: Patients receive bortezomib, dexamethasone, etoposide, ifosfamide, and
carboplatin as in the CD20-negative patients part A group.
- Part B: Patients receive rituximab IV on day 1. Patients also receive bortezomib,
dexamethasone, etoposide, ifosfamide, and carboplatin as in the CD20-negative
patients part B group. Some patients may undergo HSCT.
Patients undergo blood sample collection periodically for correlative studies. Samples are
analyzed for the effects of bortezomib on viral activation and replication via Taqman
polymerase chain reaction (PCR), and for quantification of APOBEC3G levels via western blot.
Similar studies are performed on the BCLB-1 EBV containing lines, as well as Daudi and other
EBV-transformed B-lymphocyte lines via quantitative viral DNA PCR.
Patients complete the Functional Assessment of Cancer Therapy/GOG-Neurotoxicity
Questionnaire, v4.0 at day 8 and week 4 of Part A and at least once per course of Part B for
assessment of neuropathic pain and/or peripheral neuropathy.
After completion of study treatment, patients achieving complete response (CR) are followed
at 2-4 weeks and then every 3 months for 1 year. Patients not achieving CR at completion of
study treatment and declining further antineoplastic treatment are followed at 2-4 weeks and
then every 3 months for 1 year.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose of bortezomib
Assessed at end of cycle 1 for each group of 3 subjects
Erin G. Reid, MD
University of California, San Diego
United States: Food and Drug Administration
|Memorial Sloan-Kettering Cancer Center||New York, New York 10021|
|Virginia Mason Medical Center||Seattle, Washington 98111|
|Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins||Baltimore, Maryland 21231-2410|
|Cancer Research Center of Hawaii||Honolulu, Hawaii 96813|
|USC/Norris Comprehensive Cancer Center and Hospital||Los Angeles, California 90033-0804|
|Rebecca and John Moores UCSD Cancer Center||La Jolla, California 92093-0658|
|Baylor University Medical Center - Houston||Houston, Texas 77030-2399|
|Montefiore Medical Center||Bronx, New York 10467-2490|
|University of Miami Sylvester Comprehensive Cancer Center - Miami||Miami, Florida 33136|
|Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center||Columbus, Ohio 43210-1240|
|UCLA Clinical AIDS Research and Education (CARE) Center||Los Angeles, California 90024|
|Pennsylvania Oncology Hematology Associates, Incorporated - Philadelphia||Philadelphia, Pennsylvania 19106|
|Emory Winship Cancer Institute||Atlanta, Georgia 30322|
|University of California at Davis Center for Aids Research and Education Services||Sacramento, California 95814|
|Thomas Street Health Center||Houston, Texas 77009|
|Northwestern Cancer Center||Chicago, Illinois 60611|